New paper from the Angiogenesis & Metabolism Laboratory
Blood vessel growth unleashed
Max Planck scientists discover new molecular switch for blood vessel growth
Blood vessels play an important role throughout life. Their growth (angiogenesis) is essential for normal organ development in the embryo and tissue regeneration in the adult. When blood vessel growth is deregulated, it contributes significantly to diseases such as cancer, diabetes or blinding eye disease. Scientists from the Max Planck Institute for Heart and Lung Research have now discovered a fundamental regulator of angiogenesis, which controls the metabolism of the inner vessel lining. The results of the study, which appear in the current online issue of the renowned journal Nature, could serve as the basis for new therapeutics of angiogenesis-related diseases.
Blood vessels are often compared to a plumbing system, which supply organs with oxygen and nutrient-rich blood. However, unlike rigid water pipes, blood vessels are highly adaptive and respond rapidly to changing tissue demands. A prime example is a reduction in tissue oxygen and nutrient availability, which triggers the growth of new vessel branches. Endothelial cells, which line the inner surface of blood vessels, are of particular importance for this process. Activated by growth factor signals derived from the nutrient and oxygen-deprived tissue, these cells switch from a state of dormancy to a state of accelerated cell division and growth. This switch requires an adjustment of their metabolism to provide enough energy and building blocks for cell division.
The research group of Michael Potente at the Max Planck Institute for Heart and Lung Research has now discovered a key regulator of blood vessel formation, which coordinates the growth and metabolic activity of endothelial cells. This regulator is a protein called FOXO1, a transcription factor that controls the expression of specific sets of genes. “When we genetically inactivated FOXO1 in endothelial cells of mice, uncontrolled vessel overgrowth was observed. Conversely, forced activation of this factor restricted vascular expansion”, says Potente.
Together with colleagues from Europe and the US, the scientists unraveled the underlying mechanism. They found that FOXO1 slowed endothelial proliferation and metabolism by suppressing signaling of c-MYC – a transcription factor well known to drive growth and metabolism in various types of cells. “We believe that under physiological conditions, FOXO1 represses uncontrolled cell proliferation that would impair vascular function. However, if blood vessels branches need to grow, regulation of FOXO1 activity enables a higher metabolic rate of these cells”, says Potente. In this way, adequate amounts of energy and building blocks can be made available to expand the vascular network.
An indication of the importance of FOXO1 in the endothelium arises from the fact that the protein is highly evolutionary conserved. “FOXOs are found in nematodes, fruit flies, and humans, and most cell types express the protein,” said Potente. That it has a primary function especially in endothelial cells is in Potente’s view a consequence of the particular metabolic environment in which these cells reside. “Endothelial cells are in direct contact with oxygen and nutrient-rich blood and must transfer this metabolic fuel to the surrounding tissue.” Optimal regulation of endothelial metabolism is, therefore, a prerequisite for normal vessel function reckons Potente.
According to the Max Planck researchers, FOXO1 could prove to be an attractive target for the treatment of various diseases. For instance, it is known that FOXOs are frequently inactivated in tumors. This inactivation may contribute to uncontrolled vessel formation in tumors, which is characteristic of several malignant cancers. “It might be possible to block the growth of tumors by pharmacological activation of FOXO1,” speculates Potente. The findings could also be relevant for metabolic diseases. The distinctive malfunction of the microvasculature in diabetes could be due to changes in FOXO1 signaling, says Potente.
Publication:
K. Wilhelm et al.: FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature, doi: 10.1038/nature16498, Advance Online Publication (AOP): http://www.nature.com/nature.
Contact: Dr. Michael Potente, Max Planck Institute for Heart and Lung Research, phone 06032 705 1107, email: michael.potente@mpi-bn.mpg.de
